United States Chemi cal Safety June 2012

Environmental Protection and Pollution Prevention Agency (7510P)



# Nanosilver Summary Document Registration Review: Initial Docket

June 2012Docket Number: EPA-HQ-OPP-2011-0370 www.regulations.gov

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### TABLE OF CONTENTS

Nanosilver Registration Review Team ................................................................................4 I. Preliminary Work Plan .....................................................................................................5

II. Fact Sheet ................................................................................................................ ......13 III. Summary of Anticipated Data Requirements ..............................................................17 IV. Appendix A ................................................................................................................ ..22

________________________________________

Please Note

This Preliminary Work Plan and Fact Sheet su mmarize the Environmental Protection Agency's current position based on the following documents:

1. Nanosilver: Summary of Product Chemistr y, Environmental Fate, and Ecotoxocity Effects in Support of Regi stration Review. June 22, 2012

2. Nanosilver: Summary of Human Health Effect s in Support of Registration Review. June 22, 2012

Additional supporting documents for the nanosilver ca se may be found in the registration review
docket EPA-HQ-OPP-2011-0370 located on the internet at www.regulations.gov

.Docket Number: EPA-HQ-OPP-2011-0370 www.regulations.gov

4 of 32 Nanosilver Registration Review Team

Human Health & Environmental Effects

Jed Costanza

Risk Management

Wanda Henson

Lance Wormell

Office of General Counsel

Amber Aranda Philip J. RossDocket Number: EPA-HQ-OPP-2011-0370 www.regulations.gov

5 of 32 I. Preliminary Work Plan -- Nanosilver

Introduction:

The Food Quality Protection Act (FQPA) of 1996 mandated a regi stration review program. All pesticides distributed or sold in the United St ates generally must be registered by the U.S. Environmental Protection Agency (USEPA, EPA, or the Agency ) based on scientific data showing that they will not cause unreasonable ri sks to human health or the environment when used as directed on product labeling. The regist ration review program is intended to make sure that, as the ability to assess risk evolves and as policies and practices change, all registered pesticides continue to meet th e statutory standard of no unreas onable adverse effects to human health or the environment. Changes in science, public policy, and pesticide use practices will occur over time. Through the registration review program, the Agency pe riodically reevaluates pesticides to make sure that as change occurs , products in the marketpl ace can be used safely. Information on this program is provided at http://www.epa.gov/oppsrrd1/registration_review/

.

The Agency is implementing the registration revi ew program pursuant to Section 3(g) of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and will review each registered pesticide every 15 years to determine whether it continues to meet th e FIFRA standard for registration. The Agency will consid er benefits information and data as required by FIFRA. The public phase of registration review begins when the initial docket is opened for each case. The docket is the Agency’s opportunity to state whatit knows about the pesticide and what additional risk analyses and data or information it belie ves are needed to make a registration review decision. After reviewing and responding to co mments and data received in the docket during this initial comment period, the Agency will de velop and commit to a final work plan and

schedule for the nanosilver case.

Concerning the pesticide products that will be covered by this nanosilver registration review case, EPA has information that there are silver-b ased pesticide products cu rrently in the market place that were registered without the registrant disclosing to the Agency , at the time of initial registration, the presence or characteristics of th e nanosilver in their prod ucts. In light of this information, EPA sent a letter in August of 2009 to each registrant with silver-based products requesting a statement as to whet her or not their products containe d any amount of silver in any form having a dimension that measures between 1 and approximately 100 nanometers, referred to as “nanosilver.” In response to this letter, four registrants stated that thei r products, which were registered using data for conventiona l silver (PC Code 072501), contain nanosilver, including:

1. Nanohorizons (Additive SSB, EPA Reg. No. 83587-3)

2. Garrison Dental (H2PRO, EPA Reg. No. 75829-1)

3. American Biotech Labs (ASAP-AGX, EPA Reg. No. 73499-1 and ASAP-AGX-32, EPA Reg. No. 73499-2)

4. Pool Products Packaging (Algaedyn, EPA Reg. 68161-1)

In addition, EPA is identifying the following products that were registered using data for silver chloride (PC Code 072506) as potentially containing nanosilver:Docket Number: EPA-HQ-OPP-2011-0370 www.regulations.gov

6 of 32 5. Clariant (JMAC Composite PG, EPA Reg. No. 49403-34; JM AC LP10A, EPA Reg. No. 49403-36; Nipacide JLP10, EPA Reg. No. 49403-38).

EPA is proposing to reclassify the products identi fied above as containi ng nanosilver (PC Code 072599) and include these products in this Na nosilver Registration Review case (Case No. 5042).

In addition, on December 1, 2011, EPA registered two nanosilver containing products: HeiQ AGS-20 (EPA Reg. No. 85249-1) and HeiQ AGS- 20 U (EPA Reg. No. 85249-2). Both of these products are included in this registration review case.

The Agency believes that additional data are ne eded to determine whether the FIFRA standard for maintaining these registrations is met due to nanosilver’s unique physical and chemical properties, and thus nanosilver’s potentially different he alth and safety properties as compared to silver. The Agency is establishing this Nanosilver Registration Review case pursuant to 40 CFR Part 155.42, including, but not limited to, 40 CFR 155.42(b)(2).

With the exception of the HeiQ products, EPA does not have information on the composition of the nanosilver or potential nanosilv er in the products listed above. Thus, EPA is proposing that the first phase of data submissi on be focused on determining the characteristics of the silver present in these products. If nanosilver is identifi ed during the first phase of data submission then the next phase of proposed data submission would be determining the form and concentration of silver released from the products identified to contain nanosilver. If nanosilver is found to be released from the products id entified to contain nanosilver then the final phases of data submission will concern health effects, ecological effects, and environmental fate.

The registration review of nanosilver is bei ng initiated separately from the Silver and Compounds Registration Review case (Case No. 4082, docket EPA-HQ-OPP-2009-0334 )
because EPA has determined that the information required to assess the safety of nanosilver is

different from that of silver. This determination is a presumption that is, of course, is rebuttable on a case-by-case basis. On February 29, 2012, EPA sent Data Call-In Notices (DCI) to registrants with products includ ed in the Silver and Compounds Registration Review case (Case No. 4082) requesting information on particle size. EPA is currently reviewing responses to the DCI Notice and may determine that some of th e products covered by that case and DCI should

also be included in this Nanosilver Registration Review case (Case No. 5042). Should the Agency determine that any of these products need to be included in this Nanosilver Registration Review case (Case No. 5042), it will include a st atement in the docket, and reflect that determination in the Nanosilver (Case No. 5042) Final Work Plan and in an amendment to the Silver (Case No. 4082) Final Work Plan. Shoul d the Agency subsequently determine that products listed in the Nanosilver Registration Review case be long only in the Silver and Compounds Registration Review cas e, it will include a statement in the Nanosilver Registration Review docket and reflect that determination in an amendment to the Nanosilver (Case No. 5042) Final Work Plan and in an amendment to the Silver (Case No. 4082) Final Work Plan.

Documents associated with the registration review of nanosilver can be viewed at www.regulations.gov in docke t EPA-HQ-OPP-2011-0370.Docket Number: EPA-HQ-OPP-2011-0370 www.regulations.gov

7 of 32 Anticipated Risk Assessment and Data Needs:

In November, 2009 the Agency convened a meeti ng of the FIFRA Scientific Advisory Panel (SAP) to address a number of questions associat ed with assessing the hazard of and exposure to nanosilver and other nanoscale metal-based pestic ides (FIFRA SAP, 2009). In general, the SAP advised that the toxicity of na nosilver could differ from and might be higher than other forms of silver (e.g., silver ions).

The SAP was generally unsupportive of bridging among silver-based materials with different properties. However, the SAP indicated that br idging would be appropriate for materials of similar size and essentially iden tical physical properties and that bridging between silver ions released from nanosilver and the existing database for silver ions is feasible (FIFRA SAP, 2009). The SAP cautioned about extrapolating from on e nanosilver formulation to another when assessing hazards because differences in particle formulation (e.g., coating and inert ingredients) are likely to affect biological activity, among other things.

The SAP commented that not e nough literature is available to draw any firm conclusions regarding human (occupational or consumer) and environmental exposures to nanosilver under realistic use scenarios. Potentially, three major ro utes exist for human expo sure to nanoparticles: oral, inhalation, and dermal. On ly a few studies in rodents are known that investigate the toxicity of nanosilver from exposure by these routes . Nor is there much information on the level of human exposure to nanosilver by these routes, fo r either workers or consumers using products containing nanosilver. The same situation exists for the environmental fate and transport of nanosilver. The ability to measure concentrations of nanosilver in the environment along with the environmental exposure pathways, bioavailability, toxic ity, and potential impact of nanosilver on ecological systems is not well developed. Furtherm ore, little or no information on the fate of

nanosilver in soils and sediments was found. As a result, the SAP recommended a case-by-case approach to hazard and exposure assessment (i .e., product-by-product). The SAP also advised that existing data requirements may have to be ad justed to obtain data appropriate to assess the fate, degradation, metabolism, mobility, diss ipation, and accumulation of nanomaterials.

The SAP report further suggested that existing information on conventional silver could be useful but would not necessarily be sufficient in assessing potential nanosilver risks. The SAP recommended that the Agency treat nanosilve r differently from its conventional silver counterpart in evaluating propos ed nanosilver product applications (in terms of both data requirements and the conduct of risk assessments ). Moreover, the Panel recommended that EPA require additional data on the physical chemistry, exposure potential, and the potential hazard of

nanosilver to human health and the environment.

Based on the SAP findings, the Agency anticipa tes the need to conduct a human health and ecological risk assessment if exposur e to nanosilver is anti cipated to or determined to occur. As noted later in this document, EPA anticipates th at any required data would be developed in a phased approach where product ch aracterization data would be generated prior to developing protocols for subsequent e ffects testing (See Table 2).

Product Chemistry:Docket Number: EPA-HQ-OPP-2011-0370 www.regulations.gov

8 of 32  The Agency anticipates requiring the following additional product chemistry data for the registration review of nanosilver.

830.1620/1650 – Description of Production and Formulation including specifics on milling, separation procedures, use of reducta nts or reducing atmospheres, and heating conditions. Information regardi ng the particulate size of ingr edients must be stated for each formulation step. 830.1800 -- Enforcement analytical method 830.7050 -- UV/visible light absorption Non-Guideline–Special Study: Particle Size and Diam eter (size) Distribution Non-Guideline–Special Study: Surface Area Determination Non-Guideline–Special Study: Zeta Potential Non-Guideline–Special Study: Stability to sunlight, detergents, temperature, and salinity Non-Guideline–Special St udy: Chemical Speciation Non-Guideline–Special Study: Rate of Deposition Non-Guideline–Special St udy: Dissolution Kinetics

 For more information, please refer to Nanosilver: Summary of Product Chemistry, Environmental Fate, and Ecotoxocity E ffects in Support of Registration Review , located

in the docket.

Human Health Risk:

 The Agency anticipates conducting reside ntial and occupational exposure risk assessments for the registration review of nanosilver

.

 Aggregating exposures and risks from the same pesticide requires information. Currently,

t here is insufficient information to aggregate exposures to other nanosilvers in the market place because the Agency does not have information on the composition of the other nanosilvers, their distribution in the market place, or use by consumers to determine which exposure scenarios are likely to occur together. The Agency will again examine whether sufficient information to conduct an aggregate assessment is available at the risk assessment stage of registration review for nanosilver.

 EPA does not have, at this time, adequate data to determine whether nanosilvers have common mechanisms of toxicity with each other or with other substances, or how to include these pesticides in a cumulative risk assessment.

 The Agency anticipates requiring the followi ng additional human health data for the registration review of nanosilver.

870.3100 – 90-day oral toxicity (rat) 870.3465 -- 90-day inhalati on toxicity (rat) 870.3250 -- 90-day dermal toxicity 870.3550 -- Modified Reproduction and developmenta l toxicity screenin g tests in ratsDocket Number: EPA-HQ-OPP-2011-0370 www.regulations.gov

9 of 32 Non-Guideline–Special Study: An in-vitro micronucleus assay for mutations in genetic material 875.1200 -- Dermal indoor exposure 875.1400 -- Inhalation indoor exposure Non-Guideline–Special St udy: Textile Leaching Study
Non-Guideline–Special Study: Plastics Leaching Study
Non-Guideline–Special Study: Textile Attrition Study
Non-Guideline–Special Study: Pool Water Residues

 For more information, please refer to Nanosilver: Summary of Human Health Effects in Support of Registration Review , located in the docket.

Ecological Risk:

 The Agency has not conducted a risk assessment that supports a complete endangered species determination for nanosilver. Th e ecological risk assessment planned during registration review will allow the Agency to determine whether nanosilver’s use has 'no effect' or 'may affect' federall y listed threatened or endange red species (listed species) or their designated critical hab itats. When an assessment concludes that a pesticide’s use 'may affect' a listed species or its designated cr itical habitat, the Agency will consult with

the U.S. Fish and Wildlife Service and/or National Marine Fisheries Services (the Services), as appropriate.

 The Agency anticipates requiring the follo wing additional ecological data for the registration review of nanosilver.

850.1850

-- Modified Aquatic Food Chain Transfer

850.4100

-- Terrestrial plant toxicity (seedling emergence, Tier I)

850.4400

-- Aquatic Plant Toxicity, Tier II

850.5400

-- Algal Toxicity Ti er I and Tier II Non-Guideline–Special Study: Measuring the Chronic Effects of Freshwater

Sediment-Associated Contaminants on Chironomus dilutes Non-Guideline–Special Study: Measuring the Chronic Effects of Freshwater

Sediment-Associated Contaminants on Hyalella azteca Non-Guideline–Special Study: Measuring the Chronic Effect s of Marine and Estuarine

Sediment-Associated Contaminants on Leptocheirus plumulosus

 The Agency anticipates requiring the following additional environmental fate data for the registration review of nanosilver.

835.1110 -- Activated Sludge Sorption Isotherm 850.6800 -- Modified activated sludge , respiration inhibition test

835.1230 -- Sediment and soil adsorption/desorption 835.1240 -- Leaching and adsorption/desorption Non-Guideline–Special Study: Dissolution Kinetics Study Non-Guideline–Special Study: Rate of DepositionDocket Number: EPA-HQ-OPP-2011-0370 www.regulations.gov

10 of 32  For more information, please refer to Nanosilver: Summary of Product Chemistry, Environmental Fate, and Ecotoxocity E ffects in Support of Registration Review , located

in the docket.

Timeline

EPA has created the following estimated timeline for the completion of the nanosilver registration review:

Anticipated Schedule

Activities Estimated Month/Year
Phase 1: Opening the docket
Open Public Comment Period for Docket June 2012
Close Public Comment Period for Docket August 2012
Phase 2: Case Development

Develop Final Work Plan (FWP) August 2012
Issue DCI August 2012
DCI 90-day responses due 1 November 2012

Data Submission – All data 2 August 2015

Open Public Comment Period for Prelim inary Risk Assessments January 2016
Close Public Comment Period February 2016
Phase 3: Registration Review Decision
Open Public Comment Period for Propos ed Reg. Review Decision September 2016
Close Public Comment Period for Propos ed Reg. Review Decision November 2016 Final Decision and Begin Post -Decision Follow-up March 2017
Total (years) 5

1 The 90

‐ day responses will be due to the Agency based on the date the affected registrant receives the

DCI that the Agency anticipates issuing.

2 This date reflects the last date on which required data are due, based on the schedule expected to be

included in the anticipated DCI. Earlier deadlines for submission will be included in the DCI for various

data requirements due earlier.

Registrants will have the option of using prot ocols developed as part of the HeiQ AGS-20 registration or developing their own protocols.

Guidance for Commenters:

The public is invited to comment on EPA’s Preliminary Work Plan and rationale. The Agency will carefully consider all comments as well as any additional information or data provided in a timely manner prior to issuing a final work plan for the nanosilver regi stration review case.

Trade Irritants:Docket Number: EPA-HQ-OPP-2011-0370 www.regulations.gov

11 of 32 Through the registration review process, the Ag ency intends to solicit information on trade irritants and, to the extent feas ible, take steps toward facilitating irritant resolution. Growers and other stakeholders are asked to comment on any tr ade irritant issues resulting from lack of Maximum Residue Limits (MRLs) or disparitie s between U.S. tolerances and MRLs in key export markets, providing as much specificity as possible regarding the na ture of the concern.

Water Quality:

Nanosilver is not identified as a cause of im pairment for any water bodies listed as impaired under section 303(d) of the Clean Water Act, based on information provided at http://iaspub.epa.gov/tmdl_waters10/attains_ nation_cy.cause_detail_303d?p_cause_group_id=88 5. In addition, no Total Maximum Daily Loads (TMDL) have been developed for nanosilver, based on information provided at http://iaspub.epa.gov/tmdl_waters10/attains_ nation.tmdl_pollutant_de tail?p_pollutant_group_id =885&p_pollutant_group_name=PESTICIDES.

More information on impaired wate r bodies and TMDLs can be found at http://www.epa.gov/owow/tmdl/ . The Agency invites submission of water quality data for this pesticide. To the extent possible, data should conform to the quality standards in Appendix A of

the OPP Standard Operating Procedure: Inclus ion of Impaired Water Body and Other Water Quality Data in OPP’s Registration Revi ew Risk Assessment and Management Process (see: http://www.epa.gov/oppsrrd1/regist ration_review/water_quality_sop.htm ), in order to ensure the data can be used quantitatively or qual itatively in pesticide risk assessments.

Environmental Justice:

EPA seeks to achieve environmenta l justice, the fair tr eatment and meaningful involvement of all people, regardless of race, color, national origi n, or income, in the deve lopment, implementation, and enforcement of environmental laws, regulati ons, and policies. To help address potential environmental justice issues, the Agency seeks information on any groups or segments of the population who, as a result of thei r location, cultural practices, or other factors, may have atypical, unusually high exposur e to nanosilver compared to the general population. Please comment if you are aware of any sub-populatio ns that may have atypical, unusually high exposure compared to th e general population.

Structure Activity Relationships:

EPA must rely upon information of appropriate qual ity and reliability for each decision made by the Agency. In the Office of Pesticide Program s (OPP), the evaluation process for a pesticide chemical traditionally begins with the applicant’ s submission of a set of studies conducted with the specific pesticide chemical of interest. The use of the results of such testing (measured data) is a logical, scientifically rigorous proce ss that identifies the physical, chemical, and environmental fate properties of the pesticide, as well as the dose and endpoints at which an adverse effect can occur in various animal species.

Today, there is significant interest in alternat ive techniques, i.e., tech niques other than data generation, that could significantly inform th e Agency’s decision-making process. Recently, OPP has made increasing use of structure activity relationship (S AR) as part of its regulatoryDocket Number: EPA-HQ-OPP-2011-0370 www.regulations.gov

12 of 32 decision-making process. In the SAR process, a chemical's molecular structure is compared to

that of other chemicals for which data are available. These structural similarities are then used to make predictive judgments about a chemical’s p hysical, chemical, and bi ological properties. Thus, the chemical’s physical, chemical, and biol ogical properties are a f unction of (or directly related to) the chemical’s molecular structure. Quantitative SAR is referred to as QSAR. To develop a QSAR, a selected set of measured da ta on a single physical, chemical, or biological property is used to derive a model (an equatio n) to predict the valu e of that property.

Since SAR assessments and QSAR modeling are anothe r set of tools that are available to Agency scientists, OPP has begun a process that envi sions shifting from the current study-by-study approach to an approach in which the use of pr edicted data, generated us ing validated models, is considered along with information from open litera ture and studies specifically generated under Part 161 requirements (i.e., Data Requirements for Antimicrobial Pestic ides). All relevant information would be considered as part of a weight-of-the-evidence evaluation.

At this time, EPA believes that for certain endpoints and for many ch emicals, especially physical/chemical and fate properties, SAR and QS AR might be effectivel y utilized to fulfill these data requirements for many antimicrobial pesticide chemicals. When considering biological properties, at this time, EPA believe s that SAR and QSAR can be most effectively

utilized in the evaluation of ch emicals that exhibit lower toxi city for human health and/or ecotoxicity parameters. This is appropriate because the risk assessment for lower toxicity chemicals can be stream-lined, i.e., a screening-level assessment procedure rather than multiple tiers of assessments with progres sively more data requirements.

If stakeholders believe that submission of predic ted data can fulfill one of the data needs for the nanosilver case, then the Agency invites submission of this information. The submitter would be expected to supply a rationale describing th e utility of the information and provide

documentation on the scientific valid ity of the information. The de termination that the predicted data fulfills the data requiremen t would be at the sole discretio n of the Agency. Pre-submission consultation with the Agency is encouraged.

With respect to nanosilver, EPA notes for nanos cale materials that most SAP members were generally “unsupportive of bridging among silver-based material s with different properties.” EPA asked the SAP about the applicability of SAR/QSARs for nanoscale materials and the Panel stated that “[a]s more research data become available, it might become possible to develop predictive Quantitative Structure Activity Relations hip-like models for nanomaterials. However,

such models do not exist at this time.” EPA will take the SAP statements into consideration when reviewing any arguments or data supporting the possible us e of SAR/QSAR for nanosilver products.

Additional Information:

Stakeholders are also specifically asked to provid e available information a nd data that will assist the Agency in refining its risk assessments, including any species-spec ific ecological effects determinations. The Agency is interested in receiving the following information:

1. Confirmation on the following label information:Docket Number: EPA-HQ-OPP-2011-0370 www.regulations.gov

13 of 32 a. Sites of application

b. Formulations

c. Application methods and equipment

d. Maximum application rates

e. Frequency of application, applicatio n intervals and maximum number of applications

f. Geographic limitations on use

2. Use or potential use distribution

3. Use history

4. Usage/use information for non-agricultura l uses (e.g., materials preservation)

5. Typical application interval

6. State or local use restrictions

7. Ecological incidents (non-target plant dama ge and avian, fish, reptilian, amphibian and mammalian mortalities) not already reported to the Agency

8. Monitoring data

Next Steps:

After the 60-day comment period closes in A ugust 2012, the Agency will review and respond to any comments received in a timely manner, and then issue a Final Work Plan for the nanosilver case. Additionally, the Agency plans to issue a DC I for the data at the same time it issues the

Final Work Plan.Docket Number: EPA-HQ-OPP-2011-0370 www.regulations.gov

14 of 32 II. Fact Sheet

Background Information:

 Active Ingredient: Nanosilver

 Case number: 5042

 PC Code: 072599 There are no tolerances or exemptions from requirements of a tolerance established for nanosilver used as a pesticide.

 Antimicrobials Division Chemical Revi ew Manager (CRM): Eliza Blair, blair.eliza@epa.gov

 Antimicrobials Division Product Ma nager (PM): Marshall Swindell, swindell.marshall@epa.gov

 Chemical Structure: Ag(0)

Recent/Pending Regulatory Actions:

On December 1, 2011 EPA issued conditional regist rations for two pesticide products containing nanosilver as an active ingredient. The registrations were issued to HeiQ Materials Ag (“HeiQ”) for the product HeiQ AGS-20 intended for use as a preservative in textile products (EPA Reg. Nos. 85249-1 and 85249-2). HeiQ AGS-20 contains an active ingredient, s ilver nanoparticles

also known as nanosilver. The AGS-20 nanosilver is not an active ingredie nt in any currently registered pesticide (i.e., it is a “new” active ingr edient). As part of the conditional registrations, HeiQ is required through the terms of its conditio nal registrations to provide the types of data identified in Section I: Anticipated Risk Assessment and Data Needs of this document.

Use & Usage Information:

As detailed earlier in this document, in additi on to the two HeiQ registrations that the Agency recently granted for products containing nanosilver as an active ingredient, EPA has also learned that it previously registered several silver-bas ed pesticide products without the registrant disclosing to the Agency, at the time of the re gistration, the presence or characteristics of nanosilver in the products. At present, therefore, EPA is aware that nanosilver products have been registered for the following uses: material preservatives, algaecide in swimming pools, dental unit water-line treatment, a nd hard surface disinfectants.

Ecological Risk Assessment Status:

The following are key findings from studies available in the scientific literature for nanosilver with certain size ranges and specified propert ies. This information provides a general understanding of the ecological ri sk for nanosilver; however, this information may not apply to the nanosilver in the products id entified herein. Please refer to Nanosilver: Summary of Product Chemistry, Environmental Fate, and Ecotoxoc ity Effects in Support of Registration Review

, located in the docket, for a detailed discussion of the anticipated ecological risk assessments and

data needs.

Environmental FateDocket Number: EPA-HQ-OPP-2011-0370 www.regulations.gov

15 of 32  There is a potential for nanosilver to reside or persist in the environment for a significant period of time where these par ticles are most likely to be associated with sediments. There is also the potential for nanosilver to reach publically owned wastewater treatment and privately owned septic systems where they will most likely complex with sulfide and partition to biosolids. Once entrained in the bi osolids, the nanosilver could serve as a long term source of ionic silver which may advers ely affect microorganisms that are vital to the wastewater treatment process. Because there are contradictory reports in the scientific literature on the potential for nanosilver to impact wastewater treatment operations, EPA anticipates requiring data abou t the environmental fate of nanosilver and the impact to wastewater treatment processes.

Ecotoxicity

 The ecotoxicity information available to a ssess the potential hazards of nanosilver to aquatic life is limited. There are studies in the scientific literature covering the toxicity of nanosilver to aquatic organisms. These studie s indicate to the Agency that, if sufficient quantities of nanosilver reach surface water, then exposure to nanosilver may result in adverse effects to aquatic species. Although these studies are usef ul for indicating the concentration of nanosilver that might lead to effects in aquatic species, they represent short-term (e.g., 96 hr) acute exposures and do not characterize the effects from longerterm exposure to nanosilver. Given this limitation, the Agency anticipates requiring additional data about the long-term or ch ronic ecotoxicity eff ects of nanosilver.

Human Health Risk Assessment Status:

The following are key findings from studies available in the scientific literature for nanosilver with certain size ranges and specified propert ies. This information provides a general understanding of the ecological ri sk for nanosilver; however, this information may not apply to the nanosilver in the products id entified herein. Please refer to Nanosilver: Summary of Human Health Effects in Support of Registration Review , located in the docket, for a detailed discussion of the anticipated human health risk assessment and data needs.

Hazard Characterization:

 There is little indication that nanosilver poses an acute risk to human health. While nanosilver is not anticipated to be acutely toxic, little in formation is available on the effects from long-term exposure to nanosilv er as well as poten tial reproductive and developmental effects. One study showed toxic effects in the liver a nd lungs of rats after inhalation of nanosilver. The Agency consid ers these effects adverse. Significant

increases in the amount of nanosilver in tissu es, such as olfactor y bulb, brain, kidneys, and blood, were reported. Females had two to three times more silver accumulation in their kidneys than males. This study indicate s to the Agency that, if sufficient quantities of nanosilver become airborne, and if such na noparticles display toxicity similar to the nanoparticles used in the Sung et al. (2009) study, then inhalation of nanosilver may

result in adverse health effects. As a re sult, the Agency anticipates requiring additional data about what, if any, material is released from treated tex tiles, and what, if any, effects are observed from longer term exposures.Docket Number: EPA-HQ-OPP-2011-0370 www.regulations.gov

16 of 32 Dietary (Food and Water):

 A dietary risk assessment has not been conducted because none of the products mentioned in this workplan are registered for food contact use. However, there is a potential for drinking water exposure from discharges due to use as a materials preservative, and swimming pool and dental-lin e treatment. The Agency expects that the environmental fate data that are anticipated to be required will be usef ul to evaluate this potential. Therefore, the need for a drinking water assessment will be determined after any required environmental fate data are received and reviewed.

Residential:

 Residential exposures are expected duri ng use of nanosilver-c ontaining pesticide products intended for use as or in hard surface cleaners, swimming pools, paint, and

treated articles. There is also a potential for exposure during dental treatment. Infants and

children as well as older indivi duals are also a potential s ubpopulation of exposure, based

on residential use sites as well as registered uses in day ca re facilities, during dental treatments, and hospitals. Durations of expos ure could involve short, intermediate, and long-term. Therefore, exposure data are antic ipated to be needed to assess these residential exposure scenarios.

Aggregate Exposure Assessment:

 There is insufficient information to aggregate exposures to other nanosilvers currently in the market place because the Agency does not have information on the composition of the other nanosilvers, their distribution in the market place, or use by consumers to determine which exposure scenarios are likely to occur together.

Occupational:

 Occupational exposure would be expected when handling nanosilver powder, manufacturing and processing tr eated articles, applying hard-s urface cleaners or paints by spray, mop, sponge, cloth, or brush, or during ma intenance of dental treatment lines. This exposure could involve both dermal and i nhalation exposures; therefore dermal and inhalation exposure assessments are needed for short, intermediate, and long-term exposure scenarios.

Cumulative:

 EPA does not have, at this time, adequate data to determine whether nanosilvers have common mechanisms of toxicity with each other or with other substances, or how to include these pesticides in a cumulative risk assessment.

Incidents:

Ecological:Docket Number: EPA-HQ-OPP-2011-0370 www.regulations.gov

17 of 32  No nanosilver ecological incidents have been reported in the OP P incident database.

Human Health:

 One human health incident was identified in the OPP incident data base. Nanosilver is used medically in wound dressings for pati ents suffering from burns. There is only one published report available for use by the Agen cy. In this report, a burn patient with nanosilver-coated wound dressing developed clini cal signs of argyria and elevated serum liver enzymes indicative of liver toxicity al ong with elevated silver concentrations in blood and urine (Trop, 2006).

Tolerances and International Harmonization:

There are no tolerances or exemptions from tolerances for nanosilver. Nanosilver is not approved for food contact use.

Data Call-In Status:

 There are currently no outstanding Data Call-In data requirements for the nanosilver case.

[Note: The anticipated data needs listed in this work plan are similar to those required for the conditional registrations of HeiQ AGS-20.]

Labels:

Registered products, including EP A registration numbers are provi ded in Table 1 below. For future reference, during registra tion review a list of product regi stration numbers will be included in the docket. Product registration labels may be obtained from the Pesticide Product Label System (PPLS) website at: http ://oaspub.epa.gov/pestlabl/ppls.home

.

Table 1. Registered Products – Nanosilver

Registration # Registration Name Company Name Formulation Type % A.I.

68161-1 Silver Algaedyn Pool Products Packaging Corp Nanosilver suspension 0.8

73499-1 ASAP-AGX American Biotech Labs Nanosilver suspension 0.001

73499-2 ASAP-AGX-32 American Biotech Labs Nanosilver suspension 0.0032

75829-1 H2PRO

MAINTENANCE

TREATMENT GARRISON DENTAL

SOLUTIONS Nanosilver suspension 0.0015

83587-3 ADDITIVE SSB NANOHORIZONS, INC. Nanosilver Powder 99.9Docket Number: EPA-HQ-OPP-2011-0370 www.regulations.gov

18 of 32 85249-1 HeiQ AGS-20 HeiQ Materials AG Silica-Nanosilver Composite 19.3

85249-2 HeiQ AGS-20 U HeiQ Materials AG Silica-Nanosilver Composite 19.3

Table 2. Registration Products – Pro ducts Believed to Contain Nanosilver

Registration # Registration Name Company Name Formulation Type % A.I.

49403-34 JMAC Composite PG

-orNipacide JCPG Clariant Corp Silver Chloride Powder 20

49403-36 JMAC LP10A Clariant Corp Silver Chloride suspension 2

49403-38 Nipacide JLP10 Clariant Corp Silver Chloride suspension 2

III. Summary of Anticipated Data Requirements – Nanosilver

The table below summarizes anticipated data need s for the nanosilver case in Section I of this document (Preliminary Work Plan), Nanosilver: Summary of Product Chemistry, Environmental Fate, and Ecotoxocity Effects in Support of Registration Review , and Nanosilver: Summary of Human Health Effects in Support of Registration Review

.

The current EPA Office of Chemical Safety a nd Pollution Prevention (OSCPP) and Organisation for Economic Co-operation and Development (OECD) test guidelines are based on conventional chemicals and only provide general guidance on study design issues th at might arise when testing nanomaterials. Due to the unique propert ies of nanomaterials, the Agency is initiating

efforts to revise OCSPP and OE CD guidelines so that they ar e applicable for nanomaterials. However, in the interim, in re sponding to any data requirement, whether in response to a DCI or to obtain registration, or to meet conditional regi stration requirements, registrants/applicants are encouraged to submit a protocol for each test pr ior to commencing any of the studies listed in Table 2. EPA will review these test protocols an d make suggestions rega rding details of the testing procedures. Results from any test subm itted without prior EPA pr otocol review run the risk of being graded as unacceptable if found not to, among other things, satisfy the objectives of the required testing.

EPA anticipates that any required data would be developed in a phased approach. Thus, the summary of anticipated data requi rements is separated into phases where the first phase (Phase 1Docket Number: EPA-HQ-OPP-2011-0370 www.regulations.gov

19 of 32 – Product Characteristics) is to be completed prior to the s econd phase (Phase 2 –Release Characteristics/Exposure) and third phase (Phase 3 – Health Effects) , the fourth phase (Phase 4 –

Product Characteristics of Nanosilver Released fro m Treated Article), and the final fifth phase (Phase 5 – Effects and Fate) commenced af ter the first four phases are complete

Table 2. Summary of Anticipated Data Requirements – Nanosilver

Guideline

Number Anticipated Data Requirement Test Material Estimated Timeframe for Data Submission (Measured

in months from DCI Receipt)

Phase 1: Product Characteristics TGAI

EP 7 months

Phase 2: Release Characteristics/Exposure EP 16 months

Phase 3: Product Charac teristics of Nanosilver

Released from Treated Article AIRTA* 25 months

Phase 4: Human Health Data TGAI

AIRTA* 36 months

Phase 5: Ecological and Environmental Fate Data AIRTA* 36 months

* AIRTA: Active Ingredient Release from the Treat ed Article determined during Phase 2 testing.

References

FIFRA SAP, 2009. FIFRA Scientific Advisory Pa nel Meeting held November 3 - 5, 2009 on the Evaluation of Hazard and Exposure Associated w ith Nanosilver and Other Nanometal Pesticide

Products Available at: http://www.epa.gov/scipoly/sap/meetings /2009/november/110309ameetingminutes.pdfDocket Number: EPA-HQ-OPP-2011-0370www.regulations.govIV. Appendix A: Use and Usage Information for Nanosilver Case 5042EPA RegNumberFormulation UseCategoryUse Site TreatmentSite/surfacesMethod ofApplicationMaxApplication/UseRateUse Limitations68161-1 NanosilversuspensionSwimmingPoolsPool water systems Swimming pool wateralgaeopen pour 4-16 oz. per10,000 gallons atthe rate of 8 ozper 10 minutesAdjust pH to 7.2-7.4, residualCl to 3ppm, wait 15 min. afteradding Cl before adding enduse product. This product Isnot Intended for winterizingpools.73499-1 NanosilversuspensionCommercial,institutionalandindustrialequipmentandpremisesWalls, urinals, floors,tables, chairs, lightfixtures, and bathroomsurfaces including thosemade of glass, porcelain,ceramic, enameled,painted, plastic, rubber,metal, and wood.Hard Non-poroussurfaces of inanimateobjectsMop, sponge,or clothThoroughly wetpre-cleanedsurface. 10minute contacttime at 68 F.Wipe surface withclean towel.This product is not for use onfood contact surfaces or useIn medical or health carefacilities or institutions.73499-1 NanosilversuspensionResidentialand publicaccesspremisesWalls, urinals, floors,tables, chairs, lightfixtures, and bathroomsurfaces including thosemade of glass, porcelain,ceramic, enameled,painted, plastic, rubber,metal, and wood.Hard Non-poroussurfaces of inanimateobjectsMop, sponge,or clothThoroughly wetpre-cleanedsurface. 10minute contacttime at 68 F.Wipe surface withclean towel.This product is not for use onfood contact surfaces or useIn medical or health carefacilities or institutions.Docket Number: EPA-HQ-OPP-2011-0370www.regulations.gov21 of 32EPA RegNumberFormulation UseCategoryUse Site TreatmentSite/surfacesMethod ofApplicationMaxApplication/UseRateUse Limitations73499-2 NanosilversuspensionCommercial,institutionalandindustrialequipmentandpremisesWalls, urinals, floors,tables, chairs, lightfixtures, and bathroomsurfaces made of glass,porcelain, metal, glazedceramic, enameled, andpainted surfaces.Hard Non-poroussurfaces of inanimateobjectsMop, sponge,or clothThoroughly wetpre-cleanedsurface. 10minute contacttime at 68 F.Wipe surface withclean towel.This product is not for use onfood contact surfaces.73499-2 NanosilversuspensionResidentialand publicaccesspremisesWalls, urinals, floors,tables, chairs, lightfixtures, and bathroomsurfaces made of glass,porcelain, metal, glazedceramic, enameled, andpainted surfaces.Hard Non-poroussurfaces of inanimateobjectsMop, sponge,or clothThoroughly wetpre-cleanedsurface. 10minute contacttime at 68 F.Wipe surface withclean towel.This product is not for use onfood contact surfaces.73499-2 NanosilversuspensionMedicalpremisesandequipmentWalls, urinals, floors,tables, chairs, lightfixtures, and bathroomsurfaces made of glass,porcelain, metal, glazedceramic, enameled, andpainted surfaces.Hard Non-poroussurfaces of inanimateobjectsMop, sponge,or clothThoroughly wetpre-cleanedsurface. 10minute contacttime at 68 F.Wipe surface withclean towel.This product is not for use onfood contact surfaces.Docket Number: EPA-HQ-OPP-2011-0370www.regulations.gov22 of 32EPA RegNumberFormulation UseCategoryUse Site TreatmentSite/surfacesMethod ofApplicationMaxApplication/UseRateUse Limitations73499-2 NanosilversuspensionMedicalpremisesandequipmentDental Units Dental Unit water lines Circulation Disinfection: 8oz. end useproduct to 4 ozdistilled/deionizedwater. (22 ppm)Run dental unitfor 5 minutes.Allow product toremain in unit for12 hours.Completely drainbefore use andrefill withmaintenancetreatment.Maintenance treatment: 2 oz.of end use product to 1 gallondistilled/deionized water.(0.5pppm). Mix well and filldental unit to capacity.75829-1 NanosilversuspensionMedicalpremisesandequipmentDental Units Dental Unit water lines Circulation Disinfection: addfour (1 oz) pumpsof both bottles Aand B into dentalunit. Run untilred colorationappears in supplylines. Allowproduct to remainin unit for 12hours. Completelydrain before useand refill withmaintenancetreatment.Maintenance treatment: 28oz of end use product to 7gallons of distilled/deionizedwater. Mix well and filldental unit to capacity. Rununtil blue coloration appearsin supply lines.NOTE: This EPA Reg No.covers on Bottle A of this twopart disinfection treatmentDocket Number: EPA-HQ-OPP-2011-0370www.regulations.gov23 of 32EPA RegNumberFormulation UseCategoryUse Site TreatmentSite/surfacesMethod ofApplicationMaxApplication/UseRateUse Limitations83587-3 NanosilverPowderMaterialspreservativeVitreous china,ceramics, glazes,earthenware, stoneware,dental glasses,borosilicate glasses, leadglasses, soda limeglasses, special glasses,porcelains, porcelainenamels, clays,concretes, and grouts.Toilets, sinks, urinals,bidets, lavatories,bathtubs, tile, flooring,windows, showerdoors, shower walls,shower trays, bath andkitchen accessions,countertops, handles,and knobs.Metered, openpour,incorporation1% by weight This product is not for use forfood contact applicationsDocket Number: EPA-HQ-OPP-2011-0370www.regulations.gov24 of 32EPA RegNumberFormulation UseCategoryUse Site TreatmentSite/surfacesMethod ofApplicationMaxApplication/UseRateUse Limitations83587-3 NanosilverPowderMaterialspreservativePlastics and plasticcomposite materialsincluding alkyds, aminoresins, (melamineformaldehyde and ureaformaldehyde), polyester(PET, PBT, and PEN),polyamide (Nylon),polyimide,polypropylene (PP),polyethylene (PE),polybutylene,polymethylpentene(PMP), polysiloxane,polyvinyl alcohol(PVOH), polyvinylacetate (PVA), ethylenevinyl acetate (EVA),polyethylene copolymer,polyvinyl chloride(PVC). epoxies,phenolic, polycarbonate,cellulosics, celluloseacetate, polystyrene,polyeurethane, acrylic,polymethylmethacrylate,acrylonitrile-butadienestyrene copolymer(ABS), acrylonitrilestyrene-acryliccopolyiner (ASA),acetals, polyketones,polyphelyene,Toilet seats, toilets,sinks, urinals, bidets,lavatories, bathtubs,spas, tile, flooring,shower doors, showerwalls, shower trays,bath and kitchenaccessories, plumbingsupplies and fixtures,countertops, handles,knobs, automobileparts, shower curtains,mats, protectivecovers, wastecontainers, generalpurpose containers,shower heads, mops,brooms, tapes,packaging, gaskets,pipes, tubing, pipefittings, whirlpool tuband spa components,structuralreinforcementcomposites (e.g., fiberreinforced resinbackings), furniture,HVAC parts andequipment, windowblinds, tools,keyboards, personalgrooming equipment,footwear includingboots, sportsMetered, openpour,incorporation1% by weight This product is not for use forfood contact applicationsDocket Number: EPA-HQ-OPP-2011-0370www.regulations.gov25 of 32EPA RegNumberFormulation UseCategoryUse Site TreatmentSite/surfacesMethod ofApplicationMaxApplication/UseRateUse Limitationspolyphenylene,polyphenylene sulfide,polyphenylene oxide,polysulfones, liquidcrystal polymer andflouropolymers, aminoresins, thermoplasticelastomer, rubber(including styrene,butadyene, commonacrylonitrile rubber, CR)polyacetal(polyoxymethylene), andblends and copolymerstherof.equipment, telephones,and computerequipment.Docket Number: EPA-HQ-OPP-2011-0370www.regulations.gov26 of 32EPA RegNumberFormulation UseCategoryUse Site TreatmentSite/surfacesMethod ofApplicationMaxApplication/UseRateUse Limitations83587-3 NanosilverPowderMaterialspreservativeCoatings includingalkyds, amino resins,(melamineformaldehyde and ureaformaldehyde), polyester(PET, PBT, and PEN),polyamide (Nylon),polyimide,polypropylene (PP),polyethylene (PE);polybutylene,polymethylpentene(PMP), polysiloxane,polyvinyl alcohol(PVOH), polyvinylacetate (PVA), ethylenevinyl acetate (EVA),polyethylene copolymer,polyvinyl chloride(PVC), epoxies,phenolic, polycarbonate,cellulosics, celluloseacetate, polystyrene,polyeurethane, acrylic,polymethylmethacrylate,acrylonitrile-butadienestyrene copolymer(ABS), acrylonitrilestyrene-acryliccopolymer (ASA),acetals, polyketones,polyphelylene,polyphenylene sulfide,Toilet seats, toilets,sinks, urinals, bidets,lavatories, bathtubs,spas, tile, flooring,shower doors, showerwalls, shower trays,bath and kitchenaccessories, plumbingsupplies and fixtures,countertops, handles,knobs, automobileparts, shower curtains,mats, protectivecovers, wastecontainers, generalpurpose containers,shower heads, mops,brooms, tapes,packaging, gaskets,pipes, tubing, tubefittings, whirlpool tuband spa components,structuralreinforcementcomposites (e.g., fiberreinforced resinbackings), furniture,HVAC parts andequipment, windowblinds, tools,keyboards, personalgrooming equipment,footwear includingboots, sportsMetered, openpour,incorporation1% by weight This product is not for use forfood contact applicationsDocket Number: EPA-HQ-OPP-2011-0370www.regulations.gov27 of 32EPA RegNumberFormulation UseCategoryUse Site TreatmentSite/surfacesMethod ofApplicationMaxApplication/UseRateUse Limitationspolyphenylene oxide,polysulfones, liquidcrystal polymer andflouropolymers, aminoresins, thermoplasticelastomer, rubber(including styrene,butadyene; commonacrylonitrile rubber, CR)polyacetal(polyoxymethylene), andblends and copolymersthereof.equipment, telephones,and computerequipment.Docket Number: EPA-HQ-OPP-2011-0370www.regulations.gov28 of 32EPA RegNumberFormulation UseCategoryUse Site TreatmentSite/surfacesMethod ofApplicationMaxApplication/UseRateUse Limitations83587-3 NanosilverPowderMaterialspreservativeFibers includingpolyester (“Dacron”PET, and PTT), acetate,polyolefins, polyamides(Nylon), polypropylene(PP), polyethylene (PE),polypeptides, acrylics,cellulosics, viscose,polyurethane, “Rayon”,polyvinyl alcohol(PVOH), polyvinylchloride (PVC),polyvinylidene chloride,polysaccharides, andblends and copolymersthereof.Fabrics for householdapplications such asdrapes, carpets, tableclothes and towels;home furnishings suchas chairs and bedding;automotive fabricssuch as upholstery andcarpeting; and apparelsuch as socks, shins,outwear, gloves andhats.Metered, openpour,incorporation1% by weight This product is not for use forfood contact applicationsDocket Number: EPA-HQ-OPP-2011-0370www.regulations.gov29 of 32EPA RegNumberFormulation UseCategoryUse Site TreatmentSite/surfacesMethod ofApplicationMaxApplication/UseRateUse Limitations83587-3 NanosilverPowderMaterialspreservativeAdhesives and Sealantsincluding alkyds, aminoresins, (melamineformaldehyde and ureaformaldehyde), polyester(PET, PBT, and PEN),polyamide (Nylon),polyimide,polypropylene (PP),polyethylene (PE),polybutylene,polymethylpentene(PMP), polysiloxane,polyvinyl alcohol(PVOH), polyvinylacetate (PVA), ethylenevinyl acetate (EVA),polyethylene copolymer,polyvinyl chloride(PVC), phenolic,polycarbonate,cellulosics, celluloseacetate, polystyrene,polyeurethane, acrylic,polymethylmethacrylate,acrylonitrile-butadienestyrene copolymer(ABS), acrylonitrilestyrene-acryliccopolymer (ASA),acetals, polyketones,polyphelylene,polyphenylene sulfide,Toilet seats, toilets,sinks, urinals, bidets,lavatories, bathtubs,spas, tile, flooring,shower doors, showerwalls, shower trays,bath and kitchenaccessories, plumbingsupplies and fixtures,countertops, handles,knobs, automobileparts, shower curtains,mats, protectivecovers, wastecontainers, generalpurpose containers,shower heads, mops,brooms, tapes,packaging, gaskets,pipes, tubing, pipefittings, whirlpool tuband spa components,structuralreinforcementcomposites (e.g., fiberreinforced resinbackings), furniture,HVAC parts andequipment, windowblinds, tools,keyboards, personalgrooming equipment,footwear includingboots, sportsMetered, openpour,incorporation1% by weight This product is not for use forfood contact applicationsDocket Number: EPA-HQ-OPP-2011-0370www.regulations.gov30 of 32EPA RegNumberFormulation UseCategoryUse Site TreatmentSite/surfacesMethod ofApplicationMaxApplication/UseRateUse Limitationspolyphenylene oxide,polysulfones, liquidcrystal polymer andflouropolymers, aminoresins, thermoplasticelastomer, rubber(including styrene,butadyene; commonacrylonitrile rubber, CR)polyacetal(polyoxymethylene), andblends and copolymersthereof.equipment, telephones,and computerequipment.85249-1 SilicananosilvercompositeMaterialspreservativeTextiles Apparel, carpeting,industrial textileproducts, householdtextile products,outdoor textiles,automotive textiles andupholstery.Metered, openpour,incorporation0.001-0.010% byweight.This product is not for use onfood contact surfaces.Docket Number: EPA-HQ-OPP-2011-0370www.regulations.gov31 of 32EPA RegNumberFormulation UseCategoryUse Site TreatmentSite/surfacesMethod ofApplicationMaxApplication/UseRateUse Limitations85249-2 SilicananosilvercompositeMaterialspreservativeTextiles Apparel, carpeting,industrial textileproducts, householdtextile products,outdoor textiles,automotive textiles andupholstery.Metered, openpour,incorporation0.001-0.010% byweight.This product is not for use onfood contact surfaces.49403-34 Silverchloride andinertingredientcompositeMaterialspreservativeFibers and textilesNapkins; wiping cloths;mops; towels; bags;brush bristles; filters;sponges; packagingincluding bags, sacks,wraps, cushion andabsorbent materials,containers; conveyorbelts (non food contact);apparel; commercial andindustrial wipes andfabrics; Mattress coverpads and filling; pillowcovers; sheets; blankets;fiberfill for quilts andpillows; curtains;draperies; carpet andcarpet underlay; rugs;upholstery; wallcovering fabrics;cushion pads; sleepingbags; automotive andtruck upholstery;carpeting; rear decks;Docket Number: EPA-HQ-OPP-2011-0370www.regulations.gov32 of 32EPA RegNumberFormulation UseCategoryUse Site TreatmentSite/surfacesMethod ofApplicationMaxApplication/UseRateUse Limitationstrunk liners; convertibletops; interior liners;umbrellas; outerwear;apparel:sportswear; sleepwear;trim for outerwear andgarments; stockings;socks; hosiery; caps;undergarments; innerliners for jackets; shoes;gloves and helmets;curtains, draperies,upholstery, wallcovering fabrics,artificial leather; bookcovers; sails; ropes; tentsand other outdoorequipment; tarps;awnings.